Current demographic trends indicate that the percentage of the population over 65 will double during the next three decades. Memory impairment is a frequent consequence of normal human aging that significantly compromises the quality of life for a large number of elderly individuals. The long-range goal of the present research program is to establish a nonhuman primate model for defining the neural basis of age-related cognitive decline and for developing rational approaches to treat cognitive disorders of aging. Recent comparative approaches document that the essential operating characteristic of "declarative" or "explicit" memory supported by the hippocampus are conserved across humans and experimental animals. Adopting this view, large samples of young (n=20) and aged (n=40) rhesus monkeys will be tested across procedures specifically designed to examine these mnemonic processing capacities: 1) a nonhuman primate analog of paired associate learning, 2) a transitive inference procedure measuring learning and memory for hierarchical relationships, and 3) a maze navigation task emphasizing learning and memory for complex spatial relationships. In order to document the selectivity and sensitivity of these assessments, performance will also be evaluated on several standard learning and memory procedures. These studies will provide the first systematic analysis of declarative memory function in the aged nonhuman primate, establishing an appropriate framework of evidence for relating our behavioral observations to selected hormonal and neurobiological signatures of aging. Urinary estrogen levels and the incidence of menstruation will be monitored throughout behavioral testing for all female monkeys and these data will be used to evaluate the proposal that endocrine decline exacerbates normal cognitive aging. Informed by these findings, experiments will be initiated to test the potential protective effects of hormone replacement of age-related learning and memory impairment. Studies combining immunohistochemistry and quantitative confocal laser microscopy are also proposed to determine whether declarative memory impairment is linked to the substantial loss of NMDA receptors recently documented in the aged monkey hippocampus. Bringing together the underlying themes of the research program, these studies will test the hypothesis that estrogen deficiency influences cognitive aging through effects on hippocampal glutamate receptors that mediate learning-related cellular plasticity. By this integrated approach, the proposed research is expected to substantially advance progress toward defining the interactions between cognitive, endocrine and neurobiological aging in primates.